Living cells and tissues can display high sensitivity to local micro- and nanoscale molecular and topographic patterns, including those provided in vivo by complex and well-defined structures of extracellular matrix (ECM) (Stevens M et al., (2005) Science 310:1135-1138.1). However, given the small scale of the underlying interactions, their effect on cell and tissue function is far from completely understood. Studies of engineered cell-biomaterial interactions at the subcellular, nanoscale levels are providing evidence for potential importance of submicrometer cues for cell signaling, adhesion, growth, and differentiation. However, these initial attempts at engineering control of cell function have frequently not been bioinspired or biomimetic and have failed to reproduce the multiscale effects of complex ECM structures (e.g., networks of fibers and components of the basement membrane) and associated chemical ligands, which control integrated multicellular ensembles on scales ranging from a few nanometers to hundreds of micrometers (Geiger B, et al., (2001) Nat Rev Mol Cell Biol 2:793-805, Abrams et al., (2003) Urol Res 31:341-3469, 10). Recent advances in nanofabrication techniques can enable the design and fabrication of scalable scaffolding materials mimicking the structural and mechanical cues present in the in vivo ECM environment (Park H, et al. (2007) Tissue Eng 13:1867-1877).
Heart tissue possesses complex structural organization on multiple scales, from macro- to nano-, but nanoscale control of cardiac function has not been extensively analyzed. The myocardium is an ensemble of different cell types embedded in the complex and well-defined structures of the ECM and arranged in nanoscale topographical and molecular patterns. Although the structure of cardiac tissue is highly organized in vivo, cardiomyocyte ensembles lose their native organization and adopt random distribution when cultured in vitro by using common culturing techniques, potentially compromising many of their physiological properties. A variety of methods such as mechanical stretching, microcontact printing, and electrical stimulation have been used to engineer better organized cardiomyocyte cultures. Both 2D and 3D substrata with the ˜10 μm feature size have been employed to direct cardiomyocytes into anisotropic arrangements for electrophysiological and mechanical characterization. However, it is likely that the structure and function of the in vivo cardiac tissue are regulated by much smaller, nanoscale cues provided by the ECM, which might exercise complex, multiscale control of cell and tissue function. Thus, it is important to investigate whether finer control over the cell-material interface on the nanoscale facilitates the creation of truly biomimetic cardiac tissue constructs that recapitulate the structural and functional aspects of the in vivo ventricular myocardial phenotype. In addition, the ability to robustly and reproducibly generate uniformly controlled (both structurally and functionally) and precisely defined engineered cardiac tissue will likely be necessary for eventual therapeutic products.
In this regard, the inability to direct the differentiation of multipotent progenitors specifically to mature muscle cells remains a major obstacle for optimal in vivo cardiac myogenesis during cardiac repair following injury. Furthermore, while methods of cell based therapy using cells on scaffolds exist, their use is limited benefit to the extent to which they support growth, differentiation and function of cells for a functional engineered cardiac tissue.